The long term goal of HL-71478, "Pulmonary Limitations in Chronic Heart Failure", is to understand the functional relationships between the cardiovascular and pulmonary systems, particularly as it relates to chronic heart failure (HF). This renewal focuses on a better understanding of pulmonary congestion and lung fluid balance in heart failure and its impact on respiratory system structure and function. This will be assessed through two primary aims. Aim 1) To quantify and define pulmonary congestion in humans and the impact of changes in intrathoracic fluid compartments on airway structure and function. This will be determined in HF patients according to NYHA class, body position, and exercise load, and in healthy subjects using rapid saline infusion as a model of acute congestion. Aim 2) To determine the role of beta 2 adrenergic receptors ([unreadable]2AR) in the pulmonary congestion associated with heart failure. More specifically, a) we will quantify [unreadable]2AR activity in the lungs relative to lung fluid balance and disease severity, b) determine the role of variation in the gene that encodes the [unreadable]2AR on lung fluid balance in heart failure patients and c) examine the potential benefits of acute [unreadable]-agonist therapy on lung microvascular permeability and lung water in the heart failure population. The central hypothesis of the proposal is that HF patients that have a more central distribution of fluid (expanded pulmonary capillary bed, pulmonary blood volume and bronchial circulation), evidence for increased permeability and reduced fluid removal, will have the greatest alterations in pulmonary structure and function, greater symptoms and evidence for poorer prognosis. These studies will incorporate unique imaging modalities and methods to define and quantify thoracic and pulmonary blood volume, bronchial and lung microvascular blood volume, airway lumen, airway wall and blood vessel diameters for a given airway generation. In addition we will estimate lung extravascular lung water, microvascular permeability and [unreadable]AR density. We have developed a number of novel soluble gas techniques to measure pulmonary capillary blood volume, alveolar-capillary conductance, pulmonary and bronchial blood flow as well as bronchial tissue volume. These measures combined will provide an important framework for understanding the impact of intrathoracic fluid changes on respiratory structure and ultimately physiological function. These studies are important because, 1) although pulmonary congestion is a primary feature of HF and thus a major reason for hospital admissions, it is poorly defined and understood, 2) changes in lung mechanics and gas exchange associated with congestion may be more prognostic than resting measures of cardiac function and may provide insight into optimization of therapy, 3) development of pulmonary edema (component of pulmonary congestion) is not tightly linked to the degree of cardiac dysfunction resulting in variable vulnerability among subjects, suggesting genetic factors could influence susceptibility. Thus the proposed studies will provide important information regarding the central reason heart failure patients are hospitalized and have the potential to impact therapy. PUBLIC HEALTH RELEVANCE: The long term goal of our research program is to understand the functional relationships between the cardiovascular and pulmonary systems, particularly as it relates to chronic heart failure. This renewal focuses on a better understanding of pulmonary congestion and lung fluid balance in heart failure and its impact on respiratory system structure and function. More specifically we will examine how changes in various intrathoracic fluid compartments (e.g., pulmonary blood volume, extravascular lung water, bronchial blood volume) impact airway luminal volumes and diameters, airway wall thickness and blood vessel size, and in turn how this influences pulmonary function, lung mechanics and gas exchange. In addition, we will examine the central role of the beta 2 adrenergic receptors in regulating lung fluid in the heart failure population, the impact of receptor stimulation on microvascular permeability and how receptor function and fluid regulation may be influenced by variation in the gene that encodes the beta 2 adrenergic receptor.